Hearing loss is the most common sensorineural disorder affecting at least 5 percent of population. Genetic factors are one of the most important causes for profound hearing impairment. About 1 in 2000 children are born with hereditary deafness. The bulk (around 80 percent) of genetic deafness is non-syndromic form. Studies on molecular basis of non-syndromic hearing loss (NSHL) are not only important for improving our understanding of normal hearing and hearing loss, but also for developing more precise genetic counseling and specific treatments for both genetic and environment-related hearing impairment. Because of genetic heterogeneity, large families usually from isolated communities have been selected for study that are independently capable of yielding evidence for linkage. We have collected more than 130 DNA samples from three large dominantly inherited multigenerational families in China with non-syndromic dominant deafness and have access to four additional pedigrees with NSHL that would be suitable for linkage analysis. The proposed research will exploit this unique source for large multigenerational families. We propose (1) to continue collecting samples from all available members of relevant sibships in these families, (2) to type the samples for polymorphic markers in order to exclude linkage to known loci, (3) to subject the remaining pedigrees to genome wide marker screening for linkage analysis. For the largest family NSHL.O1, linkage has been excluded to any of known loci for dominant NSHL and DNA samples from this family have already been submitted for a genome wide marker screen. We will then seek to identify and ultimately clone the relevant genes by the positional candidate gene approach. The goal of the proposed studies is to map at least one new gene for non-syndromic deafness. The proposal will provide the preliminary data required for further localization and positional cloning of the gene. This strategy has been successfully employed to map 50 loci for NSHL. This knowledge is an essential prerequisite to the development and provision of molecular diagnostic services for families with NSHL, as well as the further delineation of the functional genomics of the cochlea.